Recent BrightFocus grantees, Vinit B. Mahajan, MD, PhD, and co-investigator Jessica M. Skeie, PhD, of the University of Iowa, have published the results of their 2011-14 BrightFocus grant project in the Journal of the American Medical Association (JAMA) Ophthalmology. Skeie was first author on the paper, published online July 24 (“Proteomic Landscape of the Human Choroid-Retinal Pigment Epithelial Complex”).

The original investigation is a cutting-edge effort in the field of proteomics. They mapped the location and quantities of some 4,403 different proteins expressed in the retinal pigment epithelium (RPE) and choroid of the healthy human eye. Knowing the protein expression “landscape” could give clues as to why some regions of the eye are prone to disease, and suggest targets for future treatments, including age-related macular degeneration (AMD). BrightFocus and the National Institutes of Health were the sole funders of the project.

The paper was the featured selection in JAMA Opthalmology’s monthly “Journal Club.”

Background on their Research

Skeie and Mahajan are based at the Omics Laboratory in the university’s Department of Ophthalmology and Visual Sciences. “Omics” is a relatively new field of biology that is attempting to characterize and quantify pools of biological molecules that translate into the structure, function, and dynamics of an organism or organisms.

The RPE, a pigmented layer of cells sandwiched between the photoreceptors and the choroid, is a worthy tissue to study because of its role in changes leading to macular degeneration. Unlike the retina, which is mainly composed of photoreceptors, nerve cells that sense light and send images to the brain, the RPE consists of cells that nourish and maintain the retina. Its functions include autophagy and phagocytosis (cellular processes that remove or dissolve unwanted and/or infectious substances).

To accomplish all the tasks involved in maintenance and housekeeping for the retina, genes in the RPE express proteins that set in motion different biological chains of events, sometimes referred to as “signaling pathways.” Current thinking holds that many diseases affecting the retina, including macular degeneration, may get their start through various types of signaling gone wrong. This pathogenic cascade may be brought on by genetic susceptibility, stress (including smoking and poor nutrition), aging, and other factors that play out in the cellular environment. In the case of AMD, which stems from multiple factors, the cause is generally considered to be “all of the above.” There’s widespread agreement that the RPE is involved.

The choroid, which lies next to the RPE, is filled with blood vessels that carry nutrients and waste to and from the RPE. It is here where “choroidal neovascularization”—the out-of-control growth of fragile leaky blood vessels—starts as a symptom of wet macular degeneration. This process, too, is believed to start in the RPE, and blood vessels might be induced to grow due to “communication ‘cross‐talk’ that may exist between hundreds of proteins and chemicals,” as Mahajan and Skeie wrote in their BrightFocus grant description.

Significance of the Findings

The data published in JAMA Ophthalmolology represent an analysis of just three nondiseased donor eyes, and as such, are preliminary. “This molecular map now gives us clues why certain areas of the choroid are more sensitive to certain diseases, as well as where to target therapies and why,” Mahajan was quoted as saying in a science article featuring their research on the University of Iowa website. “Before this, we just didn’t know what was where.”

Having access to baseline information about volume and location of proteins in these important eye structures, and seeing differences in the abundance of proteins in different areas of the RPE-choroid complex, will help researchers begin to figure out which proteins may be the most critical players in vision loss and disease. The authors comment on how various parts of the eye are affected differently by disease processes, observing, for example, that the fovea, or very center of the macular responsible for the sharpest central vision in humans, is damaged by wet AMD, which has choroid involvement, but spared in most cases of dry AMD, which is characterized by retinal drusen in the early stages.

They go on to emphasize that the reason for this “regional susceptibility” in the eye is not yet known, and may be informed by proteomics findings. One common explanation holds that anatomic variation of the choroid-RPE complex is the reason why vision diseases localize; another chalks it up to higher metabolic demands imposed by the retina, which overlies the center of the eye, as opposed to the periphery.

“We considered an alternative hypothesis, that geographic differences in protein expression could make some regions prone to disease,” Skeie and Mahajan write in their paper. In their introduction, they go on to speculate about how those disease pathways might play out from a biologic and metabolic standpoint, based on existing markers.

Over time, the payoff from this type of research will come from comparing proteomic maps like theirs, which chart the landscape of normal eyes, with others mapping proteins expressed in diseased eyes, to see where and at what stages of disease protein expression varies. The variations may then become targets for interception with gene therapies or drugs. Given person-to-person variability in genes and protein expression, this field, more than others, may help usher in a new era of “personalized medicine” where customized treatment approaches are designed for individual patients.

In the meantime, Skeie and Mahajan made good use of their BrightFocus funding to provide a wealth of information about parts of the eye involved in AMD pathogenesis. That work and their publication are opening eyes to a whole new world of evidence-based science that will guide efforts to locate treatments and cures by the most direct routes.

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